Age-dependent modulation of hippocampal excitability by KCNQ-channels
Introduction
Epilepsy is a common neurological disorder afflicting 1–2% of the general population worldwide (Hauser, 1997). Hereditary factors are closely involved in the etiology of epilepsy (Hirose et al., 2000a) and genetic abnormalities have been identified in a few familial epilepsy syndromes including benign familial neonatal convulsions (BFNC) (Hirose et al., 2000a, Hirose et al., 2000b). BFNC is characterized by clusters of generalized seizures exclusively afflicting neonates, with spontaneous remission (ILAE, 1989, Aso and Watanabe, 1992, Bye, 1994, Plouin, 1997). Furthermore, it is well established that seizures of BFNC neonates often include partial seizures (Aso and Watanabe, 1992, Bye, 1994, Plouin, 1997).
Several mutations of KCNQ2 and KCNQ3, members of the KCNQ-related K+-channel (KCNQ-channel) family, have been recently identified to be associated with BFNC (Biervert et al., 1998, Charlier et al., 1998, Singh et al., 1998, Hirose et al., 2000b). Molecular biological experiments demonstrated that KCNQ2, KCNQ3 and KCNQ5 are widely co-expressed almost exclusively in the central nervous system (CNS) including the hippocampus (Biervert et al., 1998, Singh et al., 1998, Schroeder et al., 1998, Cooper et al., 2000, Smith et al., 2001). KCNQ2 and KCNQ5 are thought to fully function, when they are assembled as a heterotetramer with KCNQ3, because KCNQ2/KCNQ3 and KCNQ5/KCNQ3 heterometric channels generate 15- and 5-fold larger current than the corresponding homometric channels, respectively (Biervert et al., 1998, Schroeder et al., 1998, Schroeder et al., 2000, Tinel et al., 1998, Wang et al., 1998, Cooper et al., 2000, Schwake et al., 2000, Lerche et al., 2000). The major role of the increase in current of heterometric KCNQ-channel is thought to be an increase in surface expression of this channel, since co-expression of KCNQ2 and KCNQ3 led to a large increase in the surface expression of both KCNQ2 and KCNQ3 (Schwake et al., 2000). In addition, recent immunohistological studies indicated that KCNQ2/KCNQ3 heteromeric channel is located on proximal dendrites and soma in human hippocampal pyramidal neuron (Cooper et al., 2000). Taken together with these evidences, the pharmacological and electrophysiological profiles (voltage-dependence and kinetics) of these heterotetramer KCNQ-channels [KCNQ2/KCNQ3 (Biervert et al., 1998, Schroeder et al., 1998, Tinel et al., 1998, Wang et al., 1998, Cooper et al., 2000, Schwake et al., 2000, Smith et al., 2001) and KCNQ3/KCNQ5 (Lerche et al., 2000, Schroeder et al., 2000)] suggest that these channels contribute to the formation of native M-current, which is an important inhibitory regulator of sub-threshold neuronal excitability in CNS (Zhu et al., 2000).
Abnormalities of either KCNQ2 or KCNQ3 identified in BFNC are associated with loss of function of KCNQ-channels (Biervert et al., 1998, Charlier et al., 1998, Singh et al., 1998, Hirose et al., 2000b, Schroeder et al., 1998). Several studies have provided support for the “imbalance hypothesis”, that epileptic seizures are preceded by a relative imbalance between excitatory (i.e. glutamatergic system) and inhibitory (GABAergic system) neurotransmission (Hirose et al., 2000a). Such imbalance consequently precipitates and propagates abnormal neuronal hyperexcitability in the CNS, i.e., epilepsy. Recently, mutations in GABRG2 (encoding GABAA receptor γ2 subunit) or GABRA1 (encoding GABAA receptor α1 subunit) were identified as a cause of generalized epilepsy with febrile seizures (GEFS+) (Baulac et al., 2001), febrile seizures (FS) (Wallace et al., 2001), childhood absence epilepsy (CEA) (Wallace et al., 2001) and juvenile myoclonic epilepsy (JME) (Cossette et al., 2002). Thus, deficient function of mutant KCNQ-channels seems to cause convulsion in BFNC, consistent with the “imbalance hypothesis” (Hirose et al., 2000a). However, the pathogenic mechanisms of the age-dependent development and remission of BFNC during the neonatal period remain to be explained in relation to dysfunction of KCNQ-channels (Hirose et al., 2000a). In addition, although long term prognosis of BFNC is considered benign, individuals with BFNC have a higher risk for subsequent epilepsies (11%) compared with the general population (Plouin, 1997).
To investigate the possible relationship between deficient KCNQ-channels and age-dependent etiology of BFNC, including development, spontaneous remission and propensity for subsequent epilepsies in BFNC, the present study determined the age-dependent functional switching of KCNQ-channels, GABAergic and glutamatergic transmission in immature rat hippocampus.
Section snippets
Materials and methods
All of the experiments described in this report were performed in accordance with the specifications of the Ethical Committee of Hirosaki University and met the guidelines of the responsible governmental agency. Wistar rats (Clea, Tokyo, Japan) were housed under conditions of constant temperature at 22±2 °C with a 12-h light:12-h dark cycle.
Propagation of neuronal excitability
To investigate the possible relationship between KCNQ-deficient channels and the age-dependent etiology of BFNC, we examined the effects of KCNQ-channel, GABAergic and glutamatergic transmission system on propagation of neuronal excitability using MED64 system (Alpha MED Sciences), a novel two-dimensional neuronal electroactivity monitoring technique (Oka et al., 1999, Shimono et al., 2000, Zhu et al., 2000). To clarify the role of these neurotransmissions, each type of channel or receptor was
Discussion
Several studies on mutant KCNQ-channels suggest that none of the identified mutations in BFNC exert dominant negative effects, and consequently the reduction of M-current in BFNC patients was predicted to be small (Marrion, 1997, Biervert et al., 1998, Charlier et al., 1998, Singh et al., 1998, Schroeder et al., 1998, Schwake et al., 2000). A KCNQ2 mutant associated with BFNC (1600ins5) that has a truncated cytoplasmic carboxyl terminus did not reach the surface and failed to stimulate KCNQ3
Acknowledgements
This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (05454309, 11770532, 13670979 and 13770532), grants from Hirosaki Research Institute for Neurosciences, Pharmacopsychiatry Research Foundation, The Epilepsy Research Foundation, Uehara Memorial Foundation, Heiwa Nakajima Foundation, International Research Fund of Kyushu University School of Medicine Alumni, The Clinical Research Foundation, The
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2017, NeuropharmacologyCitation Excerpt :Flupirtine shifts the voltage required to open KCNQ type of potassium channels to a more negative potential, resulting in an increased threshold for generating a neuronal action potential (Klinger et al., 2012; Martire et al., 2004; Wladyka and Kunze, 2006). KCNQ channels are voltage gated, depolarization activated potassium channels whose expression in the brain begins before birth (Brown and Passmore, 2009; Devaux et al., 2004; Okada et al., 2003). These channels play a very important role in controlling over excitation during early life when the GABA-mediated inhibition is weak (Pena and Alavez-Perez, 2006; Peters et al., 2005).
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2015, Neuroscience LettersCitation Excerpt :The GABAergic system of the immature brain is underdeveloped compared to that of the mature brain, making it a sub-optimal target for the treatment of neonatal seizures [3,7,17,21]. Evidence from clinical and basic science research studies suggests that KCNQ potassium channels play a very important role in controlling excitation in early-life [33,35,36,39]. Flupirtine, a KCNQ channel opener [12,23,28,42], has been used clinically as an analgesic in Europe for over two decades with a good safety record.
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2014, Progress in Brain ResearchCitation Excerpt :By contrast, this happens only rarely in adulthood, when M channels are abundantly available, or an upregulation of other K+ channels helps compensate for the M-channel deficit. Furthermore, the proposed excitatory action of GABA in the immature brain could aggravate this effect (Okada et al., 2003). Namely, the intracellular concentration of Cl− ions in neurons is increased in the early postnatal period, and binding of GABA will elicit outward Cl− currents that cause membrane depolarization, just opposite to the hyperpolarizing effect of inward Cl− currents in the mature brain.
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2013, Epilepsy and BehaviorCitation Excerpt :Potassium channels play a critical inhibitory role, especially in the developing brain because of reduced levels of GABAergic inhibition. Because KCNQ (KV7) gene expression begins before birth [64,65], KCNQ channels are available to dampen the excitatory activity in the brain when GABA-mediated inhibition is weak. KCNQ channels (KCNQ1–5) are voltage-gated, depolarization-activated potassium channels, and are expressed in the nervous system [66].
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2011, Epilepsy Research